MINISTRY OF HEALTH OF UKRAINE Zaporizhzhya state medical university It is recommended on a methodical conference department of faculty pediatrics Head of the chair professor Nedel'ska S.M. "__31_" _____01______ 2020_ METHODICAL RECOMMENDATIONS FOR STUDENTS SELF WORK Educational discipline Pediatrics Module №1 Widespread somatic children diseases Substantial module Topic of lesson#12 Cardio-rheumatologic diseases in childhood Acute rheumatic fever in children. Course Faculty 4 Medical 1.Actuality of the topic: Acute rheumatic fever continues to cause a large burden of mortality and morbidity in developing countries. It is less commonindevelopedcountriesbut continues tobe seeninindigenous communities andduringoutbreaks. It is caused by an autoimmune process following infection with group A streptococci. No single test can diagnose acute rheumatic fever. Diagnosis is clinical and relies on the Jones criteria. The 5 major manifestations of acute rheumatic fever are carditis, arthritis, chorea, erythema marginatum, and subcutaneous nodules, of which the most common are carditis and arthritis. The Jones criteria were revised in 2015 to include separate criteria for low-risk and moderate- to high-risk populations. While all other manifestations of acute rheumatic fever resolve without sequelae, carditis can lead to chronic rheumatic heart disease. No treatment has been shown to alter the progression of acute rheumatic fever to chronic rheumatic heart disease. Secondary prophylaxis can improve the prognosis of established rheumatic valvular disease 2.Goals: 1. To indicate etiologic and pathophysiologic factors at acute rheumatic fever in children 2. To classify, analyze typical clinic of the acute rheumatic fever in children. 3. To make list of the examination and to analyze data of the laboratory and instrumental examination at acute rheumatic fever in children. 4. To prescribe treatment, rehabilitation, prophylaxis of the acute rheumatic fever in children. 5. To diagnose and to give the first medical aim in acute rheumatic fever in children. 6. To perform differential diagnostic of acute rheumatic fever in children 7. To make prognosis at acute rheumatic fever in children. 8. To demonstrate morally-deontological principles of the subordination in the rheumatologic department 9. Transplantation of heart. 3. Base level of training, skills and knowledge. Discipline Skills which must be got by students Anatomy, To know the anatomo-physiological features of organs of Physiology the cardiovascular system . Path. аnatomy, To define the indexes of organs of the cardiovascular system, functions of organs of the cardiovasculary system . Path. рhysiology To know the etiology and pathogenesis aspects of ARF Introduction to the child's diseases To own a research method and semiotics of diseases of organs of the cardiovascular system, leadthrough of laboratory methods; instrumental and functional methods of diagnostics. Dignostic imaging To own the instrumental methods of diagnostics of inflammation of the cardiovascular system. To appoint and estimate the results of instrumental methods of inspection. Pharmacology To write preparations: glukokortikosteroides, antibiotics, desagregants, anticoagulants, cytostatics, and other. To study indications, to prescribe and write recipes with the proper remedies Content of educational material Synonyms and related keywords: acute rheumatic fever, group A streptococci, chronic rheumatic disease. Acute rheumatic feveris an autoimmune disease following infection with group A streptococci. It affects multiple systems including the joints,the brain,the skin, and the heart.Only the effects on the heart can lead to permanentillness; chronic changes to the valves of the heart are referred to as rheumatic heart disease. Acute rheumatic fever tends to recur, leading to cumulative damage to the cardiac valvular tissue. Primary episodes of acute rheumatic fever occur mainly in children aged 5 to 14 years and are rare in people over 30 years old.More than 2.4million children have rheumatic heart diseaseworldwide; 94%ofthese are in developing countries. Worldwide there are over 330,000 new cases of acute rheumatic fever each year. Recurrent episodes remain relatively common in adolescents and young adults but uncommon in those over 35 years old.[1]Overall, itis estimated thatthere are over 25 million people affected by rheumatic heart disease,[3] leading to 345,000 deaths per year. The greatest burden of acute rheumatic fever and rheumatic heart disease is in people in developing countries and in populations of indigenous people living in poverty in industrialised countries.[4] There is no clear gender predilection for acute rheumatic fever, although rheumatic heart disease tends to be more common in females. Acute rheumatic fever is most common in tropical countrieswith no seasonal variation. There is no definitive evidence for a racial predisposition but there do appear to be hotspots, including many Pacific Island nations and among Aboriginal Australians. The highest rates of acute rheumatic fever have been documented in Aboriginal children in the Northern Territory of Australia (508 per 100,000). Asian and Pacific Islanders are over-represented among admissions for acute rheumatic fever in the US. Acute rheumatic fever was common in industrialised nations including the US until the first half of the 20th century, when the incidence decreased because of improvements in living conditions and hygiene,which in turn led to decreased transmission of group A streptococci. In the 1980s there appeared to be a resurgence in rheumatic fever in some middle-class areas of the US, thought to be related to the emergence of virulent group A streptococci belonging to M serotypes 1, 3, and 18. In addition, changing patterns of antibiotic use, in particular the movement away from using antibiotics for treating group A streptococcal pharyngitis in countries with low rates of acute rheumatic fever, may also have affected the epidemiology of groupAstreptococcal diseases. Aetiology. Acute rheumatic feveris an autoimmune disease. It is the result of an interaction between a strain of groupAstreptococci with certain undefined features that confer an ability to cause acute rheumatic fever, and a host with an inherited susceptibility. Between 3% and 6% of any population may be susceptible to acute rheumatic fever, and this proportion appears to be fairly consistent across any population. Familial clustering has been reported and twin studies indicate high heritability. Various HLA class II alleles are thought to play a role in genetic susceptibility and a particular antigen on B cells known asD8/17may act as a binding site for groupAstreptococci. There is a strong association between expression of D8/17 in populations and prevalence of rheumatic fever; however, these findings have not been universal. Interaction between group A streptococci and a susceptible host leads to an autoimmune response directed against cardiac, synovial, subcutaneous, epidermal, and neuronaltissues. Traditionalteaching states that acute rheumatic fever follows pharyngitis but not pyoderma, although this has recently been questioned. Poverty and overcrowded living conditions are key factors that contribute to the development of acute rheumatic fever through the spread of group A streptococci. Racial predisposition is debatable, as increased incidence in indigenous communities may be due to socioeconomic factors rather than genetic susceptibility. Pathophysiology Although it is clear that acute rheumatic fever is an autoimmune disease, the exact nature of the pathogenesis of acute rheumatic fever has still to be determined. It is believed that both cross-reactive antibodies and cross-reactive T cells play a role in the disease. Molecular mimicry between group A Streptococcus pyogenes antigens and human host tissue is thought to be the basis of this cross-reactivity. Putative cross-reactive epitopes on S pyogenes include the M-protein and N-acetyl glucosamine. Monoclonal antibodies against these antigens cross-react with cardiac myosin and other alpha-helical cardiac proteins such as laminin,tropomyosin, keratin, and vimentin, aswell as proteins in othertarget organs and tissues such as synovium, neuronal tissue, subcutaneous, and dermal tissues. It has been proposed that the carditis of acute rheumatic fever is initiated by cross-reactive antibodies that recognise the valve endothelium and laminin. Vascular cell adhesion-molecule-1 is up-regulated at the valve and aids in recruitment and infiltration of these T cells. The T cells initiate a predominantly TH1 response with the release of beta-interferon (IFN). Inflammation leads to neovascularisation, which allows further recruitment of T cells. It is believed that epitope spreading may occur in the valve whereby T cells respond against other cardiac tissues such as vimentin and tropomyosin, leading to granulomatous inflammation and the establishment of chronic rheumatic heart disease. Th17 cells (unique T helper cells) also appear to play an important role in the pathogenesis of acute rheumatic fever.[16] Rheumatic inflammation in the heart may affectthepericardium(oftenasymptomatic), the myocardium(rarely contributes to cardiac failure), or the endocardium (the most common and the most important [i.e., the valvular tissue]). Rheumatic granulomatous inflammation manifests in the myocardium as Aschoff bodies. These may disrupt the electrical conduction pathways leading to prolongation of the PR interval on electrocardiogram. Classification World Health Organization Expert Consultation: rheumatic fever and rheumatic heart disease, 2004[1] This commonly used schema classifies rheumatic fever into the following categories based on whether it is the first episode (primary), whether the patient has had an episode of rheumatic fever previously (recurrent), or whether the patient has established rheumatic heart disease (chronic rheumatic heart disease). Primary episode of acute rheumatic fever: a patientwithout a prior episode ofrheumatic fever andwithout evidence of established rheumatic heart disease presents with a clinical illness that meets the requirements of the Jones criteria for diagnosis of acute rheumatic fever. Recurrent episode of acute rheumatic fever: a patient who has had documented rheumatic fever in the past, but without evidence of established rheumatic heart disease, who presents with a new clinical illness that meets the requirements of the Jones criteria for diagnosis of acute rheumatic fever. Recurrent episode of acute rheumatic fever in patients with rheumatic heart disease: a patient who has evidence of established rheumatic heart disease,who presentswith a newclinical illness that meets the requirements ofthe Jones criteria for diagnosis of acute rheumatic fever. Note that the 2015 Jones criteria differ for low-risk and moderate- to high-risk populations. The criteria also allow for diagnosis of possible acute rheumatic fever (i.e., patients, generally in high-incidence settings, in whom the clinician is highly suspicious ofthe diagnosis of acute rheumatic fever, butwho do not quite meetthe Jones criteria, perhaps because full testing facilities are not available). Step-by-step diagnostic approach Acute rheumatic fever is a clinical diagnosis and there is no single diagnostic test for the disease. The most common presentation is fever and arthritis. The diagnosis requires attention to all of the manifestations of acute rheumatic fever, while considering other diagnoses for each manifestation. A useful guide to diagnosis can be found within the 2015 Jones criteria, which outlines a diagnostic approach from 4 presenting symptoms/signs: chorea, arthritis, clinical carditis, and subcutaneous nodules/erythema marginatum.[2] Another useful algorithmic approach is published by the Heart Foundation of New Zealand. [Heart Foundation of New Zealand: guide for diagnosis of acute rheumatic fever] Diagnosis of a primary episode: Jones, Kisel, Nesterov criteria The diagnosis of acute rheumatic feveris made on the basis ofidentification of major and minor clinical manifestations of the disease as detailed by the Jones criteria. There are a number of different interpretations of these criteria, and guidelines vary in different settings, most notably in areaswhere acute rheumatic fever is endemic. However,the latest revision of the Jones criteria, published in 2015, provides 2 separate sets of criteria: one for low-risk settings (i.e., those with a rheumatic fever incidence ≤2 per 100,000 school-aged children or all-age rheumatic heart disease prevalence ≤1 per 1000 population per year) and one for moderate- to high-risk populations. The diagnosis of a primary episode of acute rheumatic fever can be made if any of the following criteria are met. 1. Evidence of a recent group A streptococcal infection with at least 2 major manifestations or 1 major plus 2 minor manifestations present. 2. Rheumatic chorea: can be diagnosedwithoutthe presence of otherfeatures andwithout evidence of preceding streptococcal infection. It can occur up to 6 months after the initial infection. 3. Chronic rheumatic heart disease: establishedmitral valve disease ormixedmitral/aortic valve disease, presenting for the first time (in the absence of any symptoms suggestive of acute rheumatic fever). The 2015 criteria also allow for the diagnosis of possible rheumatic fever. This category of diagnosis allows for the situation when a given clinical presentation may not fulfil the revised Jones criteria but the clinician may still have good reason to suspect the diagnosis. Major and minor manifestations Five manifestations are considered major manifestations of acute rheumatic fever:[2] • 1. Carditis: includes carditis demonstrated only by echocardiogram (i.e., subclinical carditis). • 2. Arthritis: polyarthritis (low-risk populations) or monoarthritis or polyarthritis or polyarthralgia (moderate- to high-risk populations). 3. Chorea. 4. Erythema marginatum: pink serpiginous rash with a well-defined edge. It begins as a macule and expands with central clearing. The rash may appear and then disappear before the examiner's eyes, leading to the descriptive term of patients having 'smoke rings' beneath the skin. • 5. Subcutaneous nodules. Four manifestations are considered minor manifestations of acute rheumatic fever:[2] • 1. Fever: ≥38.5°C (≥101.3°F; low-risk populations) or ≥38.0°C (≥100.4°F; moderate- to high-risk populations. 2. Arthralgia: polyarthralgia (low-risk populations) or monoarthralgia (moderate- to highrisk populations). 3. Elevated inflammatory markers: ESR ≥60 mm/hour and/or CRP ≥28.57 nanomols/L (≥3.0 mg/dL) (low-risk populations) or ESR ≥30 mm/hour and/or CRP ≥28.57 nanomols/L (≥3.0 mg/dL) (moderate- to high-risk populations). 4. Prolonged PR interval on electrocardiogram after accounting for age variability: a prolonged PR interval that resolves over 2 to 3 weeks may be a useful diagnostic feature in cases when clinical features are not definitive. First-degree heart block sometimes leads to a junctional rhythm. Second-degree and even complete block are less common but can occur. In a resurgence of acute rheumatic fever in the US, 32% of patients had abnormal atrioventricular conduction. It is important to note that, in a patient in whom arthritis is considered a major manifestation, arthralgia cannot be counted as a minor manifestation. In a patient in whom carditis is considered as a major manifestation, a prolonged PR interval cannot be counted as a minor manifestation. Carditis: clinical presentation. Rheumatic carditis refers to the active inflammation of the myocardium, endocardium, and pericardium that occurs in rheumatic fever. While myocarditis and pericarditis may occur in rheumatic fever, the predominant manifestation of carditis is involvement of the endocardium presenting as a valvulitis, especially of the mitral and aortic valves. Carditis is diagnosed by the presence of a significant murmur, or the development of cardiac enlargement with unexplained cardiac failure, or the presence of a pericardial rub. In addition, evidence of valvulitis on echocardiogram is increasingly being considered a manifestation of carditis. Mitral regurgitation is the most common clinical manifestation of carditis and can be heard as a pan-systolic murmur loudest at the apex. Cardiac failure occurs in <10% of primary episodes of rheumatic fever. Shortness of breath may be related to cardiac failure. Pericarditis is uncommon in acute rheumatic fever and is rarely, if ever, an isolated finding. Pericarditis should be suspected in patients with chest pain, and can be confirmed clinically by the presence of a pericardial rub on auscultation. Recurrent carditis is more difficultto diagnose butis more likely ifthe first episode ofrheumatic feverincluded carditis and may be suspected by a new murmur or radiographic evidence of increased cardiac enlargement on chest x-ray. Cardiac failure is sufficient to diagnose carditis in an initial presentation but not necessarily in a recurrence unless a change in valvular regurgitation can be demonstrated by comparison with previous results. Echocardiographic evidence in the absence of clinical findings of carditis (i.e., subclinical carditis) is now considered sufficient as a major manifestation of acute rheumatic fever. There are specific Doppler and morphological findings on echocardiography that must be met.[2]. Joint involvement: clinical presentation Joint involvement occurs in upwards of 75% of cases of primary rheumatic fever, and may be a major manifestation or a minor manifestation. The classic history of joint involvement in acute rheumatic fever is one of large joint migratory polyarthritis. If the patient has monoarthritis and is suspected to have acute rheumatic fever, but does not meet the criteria for diagnosis, the patient should withhold from non-steroidal antiinflammatory drug (NSAID)treatment so thatthe appearance of migratory polyarthritis (a major manifestation) is not masked. The arthritis of acute rheumatic fever is very sensitive to salicylates such as aspirin (aswell as otherNSAIDs), and if joint symptoms do not respond within 1 to 2 days of treatment with these anti-inflammatory drugs, the diagnosis should be reconsidered. Chorea: clinical presentation In 5% to 10% of patients, chorea features as part of the acute presentation. It may also occur as an isolated finding up to 6 months after the initial group A streptococcal infection. It is also known as Sydenham chorea (named after the physician who described St. Vitus Dance in the 17th century). Thehistorymaybeof a childwhobecomes fidgety at school,followedby apparent clumsiness erraticmovements,oftenwithanassociatedhistoryof emotional alongwithuncoordinated lability andother and personality changes.Choreiform movements can affect the whole body, or just one side of the body (hemichorea). The head is often involved with erratic movements of the face that resemble grimaces, grins, and frowns; and the tongue, if affected, can resemble a 'bag of worms' when protruded, and protrusion cannot be maintained. In severe cases of chorea, this may impair the ability to eat or lead to injury or the risk of injury. Chorea disappears with sleep and is made more pronounced by purposeful movements. Typically, when asked to grip the physician's hand, the patient will be unable to maintain grip and rhythmical squeezing results. There are 2 specific signs to look for: the spooning sign is a flexion at the wrist with finger extension when the hand is extended; the pronator sign is when the palms turn outwards when held above the head. Both are consistent with chorea. Recurrence of rheumatic chorea is not uncommon, often associated with pregnancy or the oral contraceptive pill. Investigations The diagnosis of rheumatic fever requires a series of investigations. The minimum set of investigations required for suspected acute rheumatic fever is: • ESR, CRP, and white blood cell count: Australian data found that CRP and ESR were commonly elevated in patients with confirmed acute rheumatic fever (excluding chorea), whereas the leukocyte count usually was not elevated. Therefore the authors do not recommend including white cell count in the diagnosis of rheumatic fever. • Blood cultures if febrile: helps to exclude other infectious causes. • Electrocardiogram: to look for lengthening of the PR interval. Chest x-ray if clinical or echocardiographic evidence of carditis.[Fig-4] • Echocardiogram:to look for evidence ofrheumatic heart disease. The role of echocardiography in the diagnosis of acute rheumatic fever has been controversial. It is recommended that all patients with suspected acute rheumatic fever, with or without clinical evidence of carditis, should have an echocardiogram. If initially negative, it may be repeated after 1 month. It is more sensitive than clinical examination in the diagnosis of carditis in rheumatic fever, and there is accepted recognition of the importance of its use in the diagnosis of both rheumatic fever and rheumatic heart disease in the absence of clinical signs. There are published morphological and Doppler findings that are typical of rheumatic fever (see below). In addition, echocardiography can be used to investigate suspected valve damage and is useful in grading severity of carditis. • Throat culture: prior to antibiotic therapy to culture for group A Streptococcus. Less than 10% are positive, reflecting the post-infectious nature of the disease. • Anti-streptococcal serology: anti-streptolysin O and anti-DNase B titres. If the first test is not confirmatory, it should be repeated 10 to 14 days later. This is recommended in all cases of acute rheumatic fever, as throat cultures and rapid antigen tests are often negative.[Fig-5] • Rapid antigen tests: for group A Streptococcus (if available). Echocardiogram There are published morphological and Doppler findings that are typical of rheumatic fever. Doppler findings in rheumatic valvulitis • Pathological mitral regurgitation (all 4 criteria met): • Seen in at least 2 views • Jet length ≥2 cm in at least 1 view • Peak velocity >3 m/s • Pansystolic jet in at least 1 envelope. • Pathological aortic regurgitation (all 4 criteria met): • Seen in at least 2 views • Jet length ≥1 cm in at least 1 view • Peak velocity >3 m/s • Pan diastolic jet in at least 1 envelope. Morphological findings on echocardiogram in rheumatic valvulitis 1) Acute mitral valve changes • a) Annular dilation • b) Chordal elongation • c) Chordal rupture resulting in flail leaflet with severe mitral regurgitation • d) Anterior (or less commonly posterior) leaflet tip prolapse • e) Beading/nodularity of leaflet tips 2) Chronic mitral valve changes (not seen in acute carditis) • a) Leaflet thickening b) Chordal thickening and fusion c) Restricted leaflet motion d) Calcification. 3) Aortic valve changes in either acute or chronic carditis • a) Irregular or focal leaflet thickening • b) Coaptation defect • c) Restricted leaflet motion • d) Leaflet prolapse. Diagnosing recurrent rheumatic fever Recurrence of rheumatic fever, with or without evidence of established rheumatic heart disease, requires the same criteria as a primary episode. (i.e., 2 major manifestations, or 1 major plus 2 minor manifestations) or can be diagnosed with the presence of 3 minor manifestations. Diagnosis of recurrence requires evidence of a recent group A streptococcal infection. As with primary episodes, it is important that other diagnoses have been excluded. Demonstrating antecedent group A streptococcal infection Evidence of antecedent group A streptococcal infection can be shown by demonstrating 1 of the following: • 1) Elevated or rising streptococcal antibody titre • 2) Positive throat culture • 3) Positive rapid antigen test for group A streptococci • 4) Recent scarlet fever. Risk factors Strong 1) poverty • Acute rheumatic fever is a disease of poverty. The reduction in rates of rheumatic fever in the industrialised world was mostly due to changes in socioeconomic status and hygiene.[6] Although there are conflicting data from prevalence surveys regarding the link between socioeconomic indicators and rheumatic heart disease,most surveys do confirm some association with low socioeconomic status. For example, in a prevalence survey of rheumatic heart disease in children in Rajasthan, India,the prevalence ofrheumatic heart disease in the lowest socioeconomic status group was 3.9 per 1000, in the middle socioeconomic status group it was 2.1 per 1000, and in the highest socioeconomic status group no cases of rheumatic heart disease were detected. • An ecological study from New Zealand that matched hospitalisation data with census area unit data (summated data for population parcels of approximately 5000 people)found rheumatic feverrates in the most crowded quintile to be 23 times greater than that in the least crowded quintile. 2) overcrowded living quarters • Perhaps the most important environmental factor is household overcrowding. The classical studies during the 1950s in US Air Force Base barracks found that rates of acquisition of streptococcal infections increased when beds were moved closer together, thus providing a biological basis for a relationship between overcrowding and the incidence of acute rheumatic fever. 3) FHx of rheumatic fever • There is an inherited susceptibility to acute rheumatic fever. Familial clustering of cases of acute rheumatic fever have been found. Earlier twin studies found weak concordance in monozygotic twins, but a more recent meta-analysis found that the risk of rheumatic fever in a monozygotic twin with a history of rheumatic fever in the cotwin was 6 times greater than in dizygotic twins, suggesting that rheumatic fever is a disorder with a high heritability. D8/17 B cell antigen positivity • 4) The D8/17 antigen is expressed on B cells and may act as a binding site for group A streptococci on these cells. There is a strong association in a number of populations between the expression of D8/17 antigen and rheumatic fever, including in the US, Australia, Israel, Russia, Mexico, and Chile. However, this association is not universal as there has been no association found in other populations including in the US, and less strong associations in populations in India. Weak 1) HLA association • Particular HLA class II alleles appear to be associated with rheumatic fever susceptibility. HLA DRB1, DQA1, and DQB1 haplotypes were associated with rheumatic heart disease in Egyptian populations. Indigenous populations; Aboriginal Australian, Asian, and Pacific Islanders • Particular racial and ethnic groups appear to be at higher risk of acute rheumatic fever than others. However, it is not clear whether these associations are related to environmental factors such as overcrowding or an underlying inherited susceptibility. For example, inthe 1980s, SamoanchildreninHawaiiwere 88 timesmore likely to experience a first episode of acute rheumatic fever compared with white children in Hawaii (the incidence of acute rheumatic fever in Samoan children in Hawaii was 206 per 100,000). Indigenous populations are at increased risk when comparedwith nonindigenous populations in industrialised nations, includingMaori children inNewZealand and Aboriginal children in Australia. History & examination factors Key diagnostic factors 1) fever (common) • Occurs in nearly all cases at the onset of the illness. Historically, most cases will have fever above 39°C (102.2°F), but many experts suggest that 38°C (100.4°F) measured orally, rectally, or tympanic is significant. • The Jones criteria recognise fever as a minor manifestation of disease: ≥38.5°C (≥101.3°F; low-risk populations) or ≥38.0°C (≥100.4°F; moderate- to high-risk populations).[2] 2) joint pain (common) • The pain is often extreme, and if the lower limbs are affected the patient often cannot walk. The most commonly affected joints are the knees, ankles, wrists, elbows, and hips. Typically asymmetrical and usually but not always migratory. A joint may be affected for a period of hours or a couple of days. • If the patient has monoarthritis and is suspected to have acute rheumatic fever, but does not meet the criteria for diagnosis,the patient shouldwithhold from treatmentwith non-steroidal anti-inflammatory drugs (NSAIDs) so that the appearance of migratory polyarthritis (a major manifestation) is not masked. • The arthritis of acute rheumatic fever is very sensitive to salicylates such as aspirin (as well as other NSAIDs), and if joint symptoms do notrespondwithin 1 to 2 days oftreatmentwith these anti-inflammatory drugs,the diagnosis should be reconsidered. Other diagnostic factors 1) recent sore throat or scarlet fever (common) • May suggest recent group A streptococcal infection. 2) chest pain (common) • This can be a symptom of carditis. 3) shortness of breath (common) • This can be a symptom of carditis. 4) heart murmur (common). Mitral regurgitation is the most common clinical manifestation of carditis as a pan-systolic murmur heard loudest at apex and radiating to axilla. • A CareyCoombs murmur may be heard, caused by pseudo-mitral stenosis because of the increased flow of the regurgitant volume of blood over the mitral valve during diastolic filling of the left ventricle. • Aortic valvulitis manifests as aortic regurgitation and is characterised by an early diastolic murmur heard at the base of the heart, accentuated by the patient sitting forward in held expiration. • The regurgitant murmurs are heard more commonly in children and young adolescents. 5) pericardial rub (common) • If there is pericardial involvement during the acute phase of acute rheumatic fever, a pericardial rub may be heard 6) signs of cardiac failure (common) • Severe cases that are late in presentation may exhibit signs of cardiac failure due to valve damage. Cardiac failure may be presenting feature of carditis. 7) asymmetric joint swelling and/or effusion (common) • Indicates arthritis rather than arthralgia. Detection of arthritis at the hip joint can be more difficult, and careful attention should be paid to limitation of movement of the hip. The most commonly affected joints are the knees, ankles,wrists, elbows, and hips. Typically asymmetrical and usually but not always migratory.Ajoint may be affected for a period of hours or a couple of days. • The arthritis of acute rheumatic fever is very sensitive to salicylates such as aspirin (as well as other non-steroidal anti-inflammatory drugs), and if joint symptoms do not respond within 1 to 2 days of treatment with these anti-inflammatory drugs, the diagnosis should be reconsidered. 8) migratory arthritis (common) • Arthritis is usually but not always migratory. A joint may be affected for a period of hours or a couple of days and another joint may flare up as one is improving. • The arthritis of acute rheumatic fever is very sensitive to salicylates such as aspirin (as well as other non-steroidal anti-inflammatory drugs), and if joint symptoms do not respond within 1 to 2 days of treatment with these anti-inflammatory drugs, the diagnosis should be reconsidered. 9) restlessness (uncommon) • May suggest chorea, which typically affects females after a latency period of up to 6 months after group A streptococcal infection. Chorea always disappears with sleep, and is made more pronounced by purposeful movements. 10) clumsiness (uncommon) • May suggest chorea, which typically affects females after a latency period of up to 6 months after group A streptococcal infection. Chorea always disappears with sleep, and is made more pronounced by purposeful movements 11) emotional lability and personality changes (uncommon) • May suggest chorea, which typically affects females after a latency period of up to 6 months after group A streptococcal infection. Chorea always disappears with sleep, and is made more pronounced by purposeful movements 12) jerky, uncoordinated choreiform movements (uncommon) • Can affect the whole body, or just one side of the body (hemi-chorea). The head is often involved, with erratic movements of the face that resemble grimaces, grins, and frowns. Chorea always disappears with sleep, and is made more pronounced by purposeful movements. 13) inability to maintain protrusion of the tongue (uncommon) • Consistent with chorea affecting the tongue. May resemble a 'bag of worms' when protruded 14) milkmaid's grip (uncommon) • Rhythmic squeezing when the patient grasps the examiner's hands, consistent with chorea. 15) spooning sign (uncommon). • Flexion of the wrists and extension of the fingers when the hands are extended, seen with chorea. 16) pronator sign (uncommon) • Turning outwards of the arms and palms when held above the head, seen with chorea. 17) monoarthritis (uncommon) • Some patients may present with pain and swelling affecting a single joint. 18) erythema marginatum (uncommon) • Pink serpiginous rash with a well-defined edge.[Fig-8] It begins as a macule and expands with central clearing. The rash may appear and then disappear before the examiner's eyes, leading to the descriptive term of patients having 'smoke rings' beneath the skin. Rare, occurring in <5% of cases.Usually appears during the acute phase ofrheumatic fever but may recur for weeks or even months after the acute phase has subsided. May be difficult to detect in dark-skinned people. 19) subcutaneous nodules (uncommon) • Firmand painless lumps, 0.5 cmto 2 cmin diameter,foundmainly overthe extensor surfaces or bony protuberances, particularly on the hands, feet, occiput, and back. Rare, occurring in <5% of cases. Often appear after the onset of acute rheumatic fever and last from a few days to 3 weeks. 20) pregnancy or taking oral contraceptive pill (uncommon) • May be associated with recurrence of rheumatic chorea. Diagnostic tests. 1st test to order Step-by-step treatment approach No treatments affect the outcome of acute rheumatic fever. While treatment can shorten the acute inflammation, all of the various manifestations will resolve spontaneously, except for carditis. Carditis can lead to chronic rheumatic heart disease butno treatmentused inthe acute phase is preventive.[65]However, good compliancewithsecondary prophylaxis can positively alter the progression of rheumatic heart disease. Aims of management The aims of management are to: • 1) Confirm the diagnosis of acute rheumatic fever • 2) Provide symptomatic treatment and shorten the acute inflammatory phase, particularly polyarthritis, which can be very painful • 3) Provide education for the patient and the patient's family • 4) Begin secondary prophylaxis and emphasise its importance • 5) Ensure follow-up. All patients with suspected acute rheumatic fever should be admitted to the hospital so diagnosis can be confirmed, and clinical features and severity of the attack can be assessed. Some patients with a confirmed diagnosis and mild illness may be managed as outpatients after an initial period of stabilisation. With arthritis The traditionally recommendedfirst-line treatmenthasbeensalicylate therapy,primarilybasedonextensive experience with aspirin in acute rheumatic fever. 1[C]Evidence Increasingly, clinicians are recommending non-steroidal anti-inflammatory drug (NSAID) treatment. Naproxen has been used successfully, 2[C]Evidence andsome experts recommendnaproxenas first-line treatmentbecauseofits twice-dailydosing andsuperior side-effect profile, while others have successfully used ibuprofen in younger children, although there are no specific data in children with rheumatic fever. If the patient has monoarthritis and is suspected to have acute rheumatic fever, but does not meet the criteria for diagnosis,the patient shouldwithhold from salicylate therapy orNSAIDtreatment so thatthe appearance of migratory polyarthritis (a major manifestation) is not masked. Paracetamol or opioid analgesia can be given in the interim. Aspirin and NSAIDs usually have a dramatic effect on the arthritis and fever of rheumatic fever, and if unresponsive after 2 to 3 days then the diagnosis should be reconsidered. With carditis Most patients with mild or moderate carditis without cardiac failure do not require any therapy. A subset of patients with carditis who develop cardiac failure do require treatment: • • Bed rest with ambulation as tolerated • • Medical management of heart failure; first-line therapy is diuretics, and ACE inhibitors may be added in severe heart failure or where aortic regurgitation is present. Despite the absence of high-quality evidence to support the use of glucocorticoid therapy for patients with carditis and severe heart failure, there is consensus among clinicians treating rheumatic fever that the use of glucocorticoids can speed recovery. Two meta-analyses have failed to show any benefit of glucocorticoids over placebo, although contributing studies were old and generally of low quality. There is no evidence that salicylates or intravenous immunoglobulin (IVIG) improve the outcome from carditis in rheumatic fever and we do not recommend their use.[50] Rarely, a patient with atrial fibrillation may require digoxin. In the very rare circumstance of valve leaflet or chordae tendinae rupture, surgery with valve replacement may be required as a life-saving procedure. Valve repair would be the preferred surgical procedure in elective surgery for established rheumatic heart disease, butitis often not possible in acute situations because ofinflamed,friable valvular, and peri-valvular tissues. With chorea Most patients with chorea do not require treatment, as chorea is benign and selflimiting. Most symptoms resolve within weeks and almost all within 6 months. Reassurance and a quiet and calm environment often suffice. Treatment is reserved for severe chorea that puts the person at risk of injury or is extremely disabling or distressing. Valproic acid or carbamazepine may be used. Valproic acid may be more effective than carbamazepine,[74] but carbamazepine is preferred as first-line treatment because of the potential for liver toxicity with valproic acid.[39] Particular caution is required with valproic acid in females; a UK government review found that children exposed in utero to valproic acid are at a high risk of serious developmental disorders (in up to 30%-40% of cases) and/or congenital malformations (in approximately 10%of cases), and they therefore recommended that valproic acid should not be prescribed to female children, female adolescents, women of childbearing potential, or pregnant women unless other treatments are ineffective or not tolerated. Treatment may ameliorate symptoms of chorea completely, or simply reduce them. Usually it takes 1 to 2 weeks for medicine to have an effect, and itis recommended thattreatment continue for 2 to 4weeks after chorea has subsided. Haloperidol and combinations of agents should be avoided. Treatment details overview. Consult your local pharmaceutical database for comprehensive drug information including contraindications, drug interactions, and alternative dosing Complications Primary prevention Primary prevention is particularly importantin acute rheumatic fever. Primary prevention refers to appropriate and timely antibiotic treatment of a group A streptococcal respiratory tract infection. This is advised in patients with known risk factors for acute rheumatic fever, or proven group A streptococcal infection, or in populations where rheumatic fever is prevalent. If commenced within 9 days of the onset of sore throat symptoms, oral or intramuscular administration of penicillin will usually prevent the development of acute rheumatic fever.[34] Shorter courses of oral antibiotics may have comparable efficacy to standard 10-day courses of oral penicillin in treating paediatric patients with acute streptococcal pharyngitis.[35] However, there are no data regarding the prevention of rheumatic fever with these shorter courses. A metaanalysis of studies of community-based primary prevention programmes reported a reduction in risk of acute rheumatic fever by 59%. However, only 1 of the 6 studies included in the metaanalysis was a randomised controlled trial, and this did not demonstrate a statistically significant treatment effect.In low-income and middle-income countries where acute rheumatic fever is common, some experts assert that intensive sore throat surveillance and treatment programmes cannot currently be recommended as co-ordinated public health programmes because they have substantial cost implications.[38] Nonetheless, investigation and treatment of sore throat should continue to be promoted in settings where this strategy is feasible. Screening Itiswellrecognised that screening of asymptomatic populations in high-risk regions has the potentialto identify patients with mild rheumatic heart disease who may receive the greatest benefit from secondary prophylaxis.Standard screening protocols were developed by the World Health Organization and focused on screening of school-aged children. Most screening programmes have used auscultation as an initial screening procedure with follow-up echocardiography of suspected cases; however, a recent study in Cambodia and Mozambique suggested that echocardiography should be the initial procedure as auscultation may not be sufficiently sensitive.[64] Standardised guidelines for the diagnosis of rheumatic heart disease on echocardiogram were developed by an expert panel and published in 2012. Secondary prevention The main priority of long-term management is to ensure secondary prophylaxis is adhered to. Secondary prophylaxis is clinically effective and cost-effective. The WHO defines secondary prophylaxis for rheumatic fever as "the continuous administration of specific antibiotics to patientswith a previous attack ofrheumatic fever, orwell-documented rheumatic heart disease. The purpose is to prevent colonisation or infection of the upper respiratory tract with group A streptococci and the development of recurrent attacks of rheumatic fever." The most effective antibiotic is penicillin and the most effective method of delivery of penicillin is by intramuscular injection of longacting benzathine benzylpenicillin every 3 to 4 weeks.Evidence Intramuscular benzathine benzylpenicillin reduces streptococcal pharyngitis by 71% to 91% and reduces recurrent rheumatic fever by 87% to 96%. Secondary prophylaxis can reduce the clinical severity and mortality of rheumatic heart disease and lead to regression of rheumatic heart disease by about 50% to 70% if patients are adherent over a decade. The internationally accepted dosage of benzathine benzylpenicillin is the same as that for eradication of streptococci used during the acute attack. The American Heart Association recommends the same dose for both adults and children of all ages.Recommendations on the frequency ofintramuscularinjections and the duration of secondary prophylaxis vary between authorities. The WHO does not specify whether injections should be administered every 3 weeks or every 4 weeks. Some experts recommend injections every3weeks for patients athighrisk (moderate to severe carditis or previous breakthrough case of acute rheumatic fever), based on evidence that suggests that fewer recurrent episodes of acute rheumatic fever occur with this regimen.[83] The duration of secondary prophylaxis is determined by a number of factors, including age, time since last episode of acute rheumatic fever, and severity of disease. Patients with proven penicillin allergy should be managed with twice-daily oral erythromycin.[1] Penicillin is safe in pregnancy[1] andintramuscularinjectionsofbenzathinebenzylpenicillinare consideredsufficiently safe for anticoagulated patients. Updated guidelines from the American Heart Association (AHA) do not recommend antibiotic prophylaxis for rheumatic heart disease patients prior to dental or surgical procedures for the prevention of infective endocarditis, but this is not universally accepted. In Australia, patients with rheumatic heart disease, including non-indigenous patients, have been found to have a substantially increased risk of endocarditis. 'The National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand recommend that if taking penicillin for secondary prophylaxis, clindamycin can be given for dental procedures in a dose of 15 mg/kg (maximum 600 mg) orally or intravenously as a single dose prior to the procedure.[39] Pneumococcal and influenza vaccination may be considered in patients specifically with heart failure Prognosis Acute recovery without treatment Left untreated, acute rheumatic fever usually resolves within 12 weeks Acute recovery with treatment With treatment, the symptoms of acute rheumatic fever should resolve within 2 weeks but cardiac inflammation lasts weeks to months. It is not uncommon for patients to have an apparent relapse early after the first attack, particularly as they are weaned away from salicylates or glucocorticoids; this relapse may include return of arthritis or arthralgia, with fever and elevated inflammatorymarkers. This doesnotindicate a recurrence and canbe easilymanagedwithre-institution of anti-inflammatory medicine from which patients can be weaned at a slower pace. Long-term sequelae Patients with acute rheumatic fever should expect to make a complete recovery from the arthritis, fever, and chorea. Patients should be warned that, in the long term, they are at risk of chronic rheumatic heart disease and they are at risk of repeated episodes of acute rheumatic fever. The likelihood of developing rheumatic heart disease depends upon the severity of the initial attack of acute rheumatic fever and the number of recurrent episodes of rheumatic fever. Around 30% to 50% of all patients with rheumatic fever will develop rheumatic heart disease, and this risk increases to more than 70% ifthe initial attack is severe or ifthere has been atleast one recurrence. Therefore, secondary prophylaxis to prevent recurrent attacks is very important, particularly as 75% of recurrences occur within 2 years of the first attack and more than 90% occur within the first 5 years. A first attack not involving the heart does not necessarily mean that subsequent attacks will also spare the heart.[45] The proportion of patients with a primary episode of acute rheumatic feverthat develop a recurrence varies depending upon compliancewith secondary prophylaxis; in areaswhere compliance is poor, up to 45% of cases of rheumatic fever are recurrent episodes. Intramuscular benzathine benzylpenicillin reduces streptococcal pharyngitis by 71% to 91% and reduces recurrent rheumatic fever by 87% to 96%.Secondary prophylaxis can reduce the clinical severity and mortality of rheumatic heart disease and lead to regression of rheumatic heart disease by about 50% to 70% if patients are adherent over a decade. 6. Additions. Control of knowledge Questions 1. Definition of the acute rheumatic fever and chronic rheumatic disease in children. 2. Classification acute rheumatic fever. 3. What causes acute rheumatic fever? 4. What causes acute and chronic heart failure? 5. Clinical forms acute rheumatic fever. 6. Clinical manifestations. Diagnosis. 7. What are the methods of the acute rheumatic fever management? 8. Will antibiotics help to control acute rheumatic fever? 9. Rational antibiotic and hormone treatment. 10. Physiotherapy. 11. Transplantation of heart, other surgical treatment. Tasks Task 1 A 10-year-old female presents with a 2-day history of fever and sore joints. Further questioning reveals that she had a sore throat 3 weeks ago but did not seek any medical help at this time. Her current illness began with fever and a sore and swollen right knee that was very painful. The following day her knee improved but her left elbow became sore and swollen. While in the waiting room her left knee is now also becoming sore and swollen. ECG was done at the admission: 1. Make primary diagnosis 2. Make plan of laboratory and instrumental tests to be done 3. Propose treatment plan Task 2 A 8-year-old female became fidgety at school, followed by apparent clumsiness alongwith uncoordinated and erratic movements, oftenwith an associated history of emotional lability and other personality changes. At the examination erratic movements of the face that resemble grimaces, grins, and frowns; and the tongue. Further questioning reveals that she had a sore throat 10 weeks ago but did not seek any medical help at that time. Serum ASO titre is 600 units. 1. What is your primary diagnosis? 2. Which lab tests are needed to prove diagnosis? 3. Choose the proper treatment Correct answers Task 1 1) Acute rheumatic fever, complete heart block. 2) ESR, CBC, ECG, EchoCG, Chest X-ray, throat culture, rapid antigen test for group A streptococci, anti-streptococcal serology 3) Regimen – strict bed, diet -#7, antibiotic therapy, analgesia, salicylate therapyor NSAIDs, diuretic/ACE inhibitors, antiarythmic theapy, follow up secondary prophylaxis. Task 2 1) Acute rheumatic fever, chorea 2) ESR, CBC, ECG, EchoCG, Chest X-ray, throat culture, rapid antigen test for group A streptococci, anti-streptococcal serology 3) Regimen – strict bed, diet -#7, antibiotic therapy, anticonvulsants, follow up secondary prophylaxis. TESTS. Primary control. 1. Acute rheumatic fever is A. infectious disease caused by group A streptococci B. disease caused by trauma C. an autoimmune disease following infection with group A streptococci 2. What is referred as rheumatic heart disease? A. subacute heart failure B. chronic changes to the valves of the heart C. mitral valve prolapse 3. Acute rheumatic fever affects multiple systems including the next: A. the joints, the heart, the brain, the muscular system B. the joints, the brain, the skin, and the heart C. the joints, the skin, the throat, the immune system 4. What is thought to play a role in genetic susceptibility to Acute rheumatic fever? A. Various group A streptococci strains B. Various throat structures C. Various HLA class II alleles 5. What may act as a binding site for group A streptococci? A. a particular antigen on B cells known as D8/17* B. a particular group A streptococci strain C. a particular T cell type 6. What are the key factors that contribute to the development of acute rheumatic fever through the spread of group A streptococci? A. Virulent properties of group A streptococci B. Patient’s age and sex C. Poverty and overcrowded living conditions 7. What is the key part of the pathophysiology of the Acute rheumatic fever? A. It is believed that some environmental factors can contribute to the Acute rheumatic fever development. B. It is believed that both cross-reactive antibodies and cross-reactive T cells play a role in the disease 8. Which statement is correct? A. Acute rheumatic fever can be easily diagnosed with Echocardiography B. Acute rheumatic fever is the diagnosis of exclusion C. Acute rheumatic fever a laboratory diagnosis and there is no single specific clinical symptom D. Acute rheumatic fever is a clinical diagnosis and there is no single diagnostic test for the disease. 9. What is the most common presentation of Acute rheumatic fever? A. carditis and chorea B. carditis and fever C. fever and arthritis D. arthritis and chorea 10. Which regimen of the antibacterial treatment is preferable for the primary Acute rheumatic fever prophylaxis? A. 5-day courses of oral penicillin within 35 days of the onset of sore throat symptoms B. 3-day courses of oral penicillin within 2 days of the onset of sore throat symptoms C. 10-day courses of oral penicillin within 9 days of the onset of sore throat symptoms TESTS. Final control. 1. The WHO defines secondary prophylaxis for rheumatic fever as "the continuous administration of specific antibiotics to patients with a previous attack of rheumatic fever, or well-documented rheumatic heart disease. What is the purpose of this treatment? A. to prevent colonisation or infection of the upper respiratory tract with group A streptococci and the development of recurrent attacks of rheumatic fever B. to prevent recurrent tonsillitis and chronic rheumatic fever 2. What is the most effective regimen of the secondary prophylaxis? A. delivery of long-acting benzathine benzylpenicillin by intramuscular injection every 3 to 4 weeks* B. delivery of penicillin by intramuscular injection every 3 to 4 months. C. delivery of long-acting macrolydes by intramuscular injection every 3 to 4 weeks 3. Patients with proven penicillin allergy should be managed with A. long-acting benzathine benzylpenicillin by intramuscular injection B. oral cephalosporin C. oral erythromycin D. long-acting macrolydes by intramuscular injection 4. Which ECG finding can be considered as a criterion of the ARF? A. Prolonged PR interval B. Complete AV blocage C. Sinus rhythm D. Atrial fibrillation 5. Choose the correct stement: A. in a patient in whom carditis is considered a major manifestation, arthralgia cannot be counted as a minor manifestation B. in a patient in whom arthritis is considered a major manifestation, arthralgia cannot be counted as a minor manifestation C. in a patient in whom chorea is considered a major manifestation, myalgia cannot be counted as a minor manifestation D. in a patient in whom subcutaneous noduls are considered a major manifestation, fever cannot be counted as a minor manifestation 6. Male patient 8 y.o. was admitted to the hospital with complaines on fever, swelling of the knee, painful movement in the knee. Treatment was started 2 days ago with penicillin orally and oilment with anti-inflammatory drug (NSAID) locally on the knee, but there is no positive changes. What further tactics should be considered in this case? A. Continue treatment B. Antibacterial drug must be changed C. The diagnosis should be reconsidered D. To add oilment with glucocorticosteroids 7. Female patiet 9 y.o. was admitted to the hospital with complains on fatigue, erratic movements, clumsiness, emotional lability. Rapid antigen tests: for group A Streptococcus is negative, ASO titre 160 units, throat cultures are negative. What further tactics should be considered in this case? A. Diagnosis ARF should be reconsidered B. Tests should be repeated 10 to 14 days later C. Diagnosis ARF can be proven only with clinical symptoms, no other tests are needed 8. Which from the listed below can be considered as specific for the ARF? A. The most commonly affected joints are the knees, ankles, wrists, elbows, and hips B. Typically symmetrical join affection and usually but not always stable. C. A joint may be affected for a period of weeks or a couple of years. D. The most commonly affected joints are the fingers 9. Which from the listed below can NOT be considered as diagnostic criterion for the ARF? A. rapid antigen test for group A streptococci B. C-reactive protein C. anti-streptolysin O titre D. anti-deoxyribonuclease B titre E. rheumatic factor 10. Choose the best treatment tactics for patient with ARF carditis who was already prescribed penicillin orally. A. To add nonsteroidal anti-inflammatory drugs B. To add furosemide C. To add prednisolone D. To add carbamazepine Answers: Primary tests: 1-C, 2-B, 3-B, 4- C, 5-A, 6-C, 7-B, 8-D, 9-C, 10-C. Final tests: 1-A, 2-A, 3-C, 4-A, 5-A, 6-C, 7-B, 8-A, 9-E, 10-B. 7. Reference 1. Kliegman R. M., Geme J. St. Nelson Textbook of Pediatrics, 2-Volume Set, 21st Edition, Elsevier, 2019. - 4264 p. 2. Pediatrics: textbook (IV a. l.) / T.O. Kryuchko, O.Y. Abaturov, T.V. Kushnereva et al.; edited by T.O. Kryuchko, O.Y. Abaturov. — 2nd edition, revised = Педіатрія, 2017. – 208 p. 3. Ghai O.P. Esential Pediatrics. Eighth Edition: 2013. – 783 p. 4. Pediatrics. Textbook. / O.V. Tiazhka, T.V. Pochinok, A.N. Antoshkina et al. / edited by O.Tiazhka, - Vinnytsia : Nova Knyha Publishers, 2011 – 584 pp. 5. Piyush Gupta, V.V. Paul Essential pediatrics- Textbook for students and practitioners.- 6 Ed.New Delhi. - 2008. - 719 p 6. Acute rheumatic fever // BMJ Learning. – 2017, 7. World Health Organization. Rheumatic fever and rheumatic heart disease: report of a WHO Expert Consultation. 2004. http://www.who.int (last accessed 24 June 2016). 8. Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131:1806-1818. 9. Carapetis JR, Steer AC, Mulholland EK, et al. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5:685-694. 10. Miyake CY, Gauvreau K, Tani LY, et al. Characteristics of children discharged from hospitals in the United States in 2000 with the diagnosis of acute rheumatic fever. Pediatrics. 2007;120:503-508. 11. Engel ME, Stander R, Vogel J, et al. Genetic susceptibility to acute rheumatic fever: a systematic review and meta-analysis of twin studies. PLoS One. 2011;6:e25326 12. Kumar V, FaustoN, Abbas A. Robbins & Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, PA: Saunders; 2004 13. Jaine R, Baker M, Venugopal K. Acute rheumatic fever associated with household crowding in a developed country. Pediatr Infect Dis J. 2011;30:315-319 14. Nelson Textbook of Pediatrics, XX Edition. - Expert Consult Premium Edition - Enhanced Online Features and Print / by Robert M. Kliegman, MD, Bonita M.D. Stanton, MD, Joseph St. Geme, Nina Schor, MD, PhD and Richard E. Behrman, MD. - 2016. - 2680 p. 15. Local relevant literature: 16. Pediatrics: Manual on Faculty Pediatrics for Foreign Students/Y.V. Odynets, A.F. Ruchko, I.N. Poddubnaya. – Kharkov: «Kruk», 2003.-224p. 17. Pediatric clinical methods/Kaushal Singh. – SAGAR PUBLICATIONS, 2006. – 333p. 18. Basic Clinical Pediatrics/Mohammed El-Naggar. – National library, 2006. – 84p. 19. Pediatrics / Edited by O.V. Tiazhka, T.V. Pochinok, A.M. Antoshkina/ - Vinnytsa: Nova Knyha Publishers, 2011. - 584 p.